Altered photic and non-photic phase shifts in 5-HT(1A) receptor knockout mice.
The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) is thought to be modulated by 5-HT. 5-HT is though to inhibit photic phase shifts by inhibiting the release of glutamate from retinal terminals, as well as by decreasing the responsiveness of retinorecipient cells in the SCN. Furthermore, there is also evidence that 5-HT may underlie, in part, non-photic phase shifts of the circadian system. Understanding the mechanism by which 5-HT accomplishes these goals is complicated by the wide variety of 5-HT receptors found in the SCN, the heterogeneous organization of both the circadian clock and the location of 5-HT receptors, and by a lack of sufficiently selective pharmacological agents for the 5-HT receptors of interest. Genetically modified animals engineered to lack a specific 5-HT receptor present an alternative avenue of investigation to understand how 5-HT regulates the circadian system. Here we examine behavioral and molecular responses to both photic and non-photic stimuli in mice lacking the 5-HT(1A) receptor. When compared with wild-type controls, these mice exhibit larger phase advances to a short late-night light pulse and larger delays to long 12 h light pulses that span the whole subjective night. Fos and mPer1 expression in the retinorecipient SCN is significantly attenuated following late-night light pulses in the 5-HT(1A) knockout animals. Finally, non-photic phase shifts to (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) are lost in the knockout animals, while attenuation of the phase shift to the long light pulse due to rebound activity following a wheel lock is unaffected. These findings suggest that the 5-HT(1A) receptor plays an inhibitory role in behavioral phase shifts, a facilitatory role in light-induced gene expression, a necessary role in phase shifts to 8-OH-DPAT, and is not necessary for activity-induced phase advances that oppose photic phase shifts to long light pulses.
Smith
V M
VM
Department of Psychology, University of Calgary, 2500 University Drive Northwest, Calgary, Alberta, Canada T2N 1N4.
Sterniczuk
R
R
Phillips
C I
CI
Antle
M C
MC
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics*; D019886:Gastrin-Releasing Peptide / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D010775:Photic Stimulation / Q000379:methods; D017440:Photoperiod; D044282:Receptor, Serotonin, 5-HT1A / Q000172:deficiency*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D016761:Oncogene Proteins v-fos; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D014660:Vasoactive Intestinal Peptide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D019886:Gastrin-Releasing Peptide